Intravaginal drug delivery can be utilized for topical, local, or systemic effects. Topical administration has been used to treat various bacterial or fungal infections, atrophic vaginitis, and vaginal intraepithelial neoplasia. The most relevant prior art to the instant invention was the subject of a few patent applications by one of the present inventors. The most recent application, U.S. Ser. No. 11/974,140 (filed on Oct. 11, 2007) is directed with a ring device having multicomponent drug releasing substrates loaded with at least one bioactive agent and designed to effect contraception and/or provide means to treat and/or prevent diseases caused by infectious bacteria, fungi, virus, and retroviruses, without compromising the primary function of normally occurring, useful vaginal microflora in female patients. This application was a continuation-in-part of U.S. Ser. No. 11/667,933, filed on May 16, 2007, and entitled “Intravaginal Ringed-mesh Device and Applicator Therefor.” The tenets of the prior art that preceded U.S. patent application Ser. No. 11/974,140, and related disclosures which are also relevant to this invention are outlined below.
U.S. application Ser. No. 10/860,677, hereby incorporated herein by reference in its entirety, discloses a controlled drug release device comprising a partially or fully absorbable, fiber-reinforced composite ring system comprising an absorbable or non-absorbable matrix, an absorbable, reinforcing fibrous construct and an absorbable coating to provide three modes of controlling the release of bioactive agents and one mode for modulating the mechanical property of the ring in a body cavity during device functional use. For partially absorbable ring systems, the drug release is dependent initially on the diffusion rate of the drug through the matrix and the absorbable coating. As the latter degrades with time, the diffusion through the matrix prevails. Meanwhile, as the absorbable fibrous reinforcing construct undergoes degradation with time, the mechanical strength of the composite ring decreases to provide the desired mechanical strength retention profile. For a fully absorbable composite ring system, the degradation of the matrix offers an additional mode of controlling the release profile as compared with the partially absorbable counterpart. In effect, the invention of U.S. application Ser. No. 10/860,677 deals with a fiber-reinforced composite ring system for the controlled release of at least one bioactive agent comprising a biocompatible matrix reinforced with an absorbable/biodegradable fibrous construct capable of providing the mechanical properties needed for inserting and maintaining said ring in a body cavity for the desired period of time, wherein the absorbable/biodegradable reinforcing fibers are made primarily from at least one cyclic monomer such as glycolide, l-lactide, ε-caprolactone, p-dioxanone, and trimethylene carbonate.
U.S. application Ser. No. 10/935,808 was filed on Sep. 8, 2004 as a continuation-in-part application of U.S. Ser. No. 10/860,677, described above, and dealt with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent. The composite included an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of the bioactive agent for the desired period of time at a specific biological site. In accordance with that invention (1) the absorbable reinforcing fibers were formed from at least one cyclic monomer selected from glycolide, l-lactide, ε-caprolactone, p-dioxanone, trimethylene carbonate, and a morpholine-2,5-dione; and (2) the biostable matrix was made of a polyether urethane elastomer or a silicone elastomer, such as a copolymer polysiloxane, including dimethyl siloxane sequences, which can be one of the Silastic® family of silicone elastomers.
Obviously, application Ser. Nos. 10/860,677 and 10/935,808 and related teachings did not disclose (1) the use of a non-absorbable reinforcing construct in the composite ring; (2) a novel cross-sectional geometry of the ring and associated clinical benefits in terms of ease of placement and minimized vaginal tissue trauma; (3) use of a novel feature entailing the presence of a mesh encircled by the composite ring, wherein such mesh can be used as a spermiostatic net in a contraceptive device and/or a depot for the release of bioactive agents including antimicrobials and antivirals; and (4) a ring applicator that can be used as needed by the patient without physician intervention. This led to a series of related applications, namely U.S. provisional application No. 60/635,887, filed on Dec. 14, 2004, PCT Application No. U.S. 05/45190, filed on Dec. 14, 2005, and U.S. application Ser. No. 11/667,933, filed on May 16, 2007, hereby incorporated herein by reference in its entirety.
U.S. application Ser. No. 11/667,933 is directed in general to an intravaginal device which is a ringed, flat mesh encircled with a fiber-reinforced composite ring, the composite ring providing for the controlled delivery of at least one bioactive agent, the ring being formed of a fibrous construct contained within a compliant, elastomeric copolymeric matrix, the fibrous construct providing adequate stiffness and resilience for in-use biomechanical stability, the copolymeric matrix further containing solid excipients to modulate the pH about the ring and the concentration of the at least one bioactive agent. More specifically, this case is directed to an intravaginal device comprising a ringed, flat mesh encircled with a fiber-reinforced composite ring for the controlled delivery of at least one bioactive agent. The ring is a fibrous construct that is capable of imparting needed stiffness, resilience, and in-use biomechanical stability to the compliant elastomeric copolymeric matrix thereof containing solid excipients to modulate the pH of the aqueous eluates and concentration of the bioactive agent or agents released therein. The mesh is a biostable, non-woven, melt-blown, porous polyolefin fabric, such as those made of polyethylene or polypropylene, having an average pore diameter of less than 100 microns and preferably less than 20 microns and more preferably less than 7 microns and the encircling ring is made of a crosslinked silicone elastomeric copolymer reinforced with a circular band of high-melting multifilament yarn sized with a low-melting polymer. In a specific situation, the flat fabric mesh is made of melt-blown fabric comprising polypropylene microdenier fibers and the fiber-reinforced composite ring is a crosslinked silicone elastomer reinforced with polyethylene terephthalate multifilament band sized with poly-ε-caprolactone wherein the matrix contains ferrous gluconate or ferrous ascorbate as a spermiostatic/spermicidal agent and at least one excipient selected from the group represented by ascorbic acid, carboxyl-bearing polyglycolide, glycine, citric acid, oxalic acid, tartaric acid, and glycolic acid. Because of its composition and design, the intravaginal device is conceived as a multifaceted, biomechanically, biochemically, and pharmacologically active device for securing contraception in humans and animals. A key feature of such device and particularly the flat mesh is that the polypropylene fibers of the mesh are surface sulfonated to repel approaching negatively charged sperms. This is associated with the fact that the sperms have a negatively charged surface that will be repelled by the negatively charged sulfonate-bearing surface of the mesh. This and the limited porosity of the mesh, which can be associated with a pore diameter of less than 7 microns, will prevent the sperm diffusion through the mesh as the sperm has a head diameter of about 7 microns. Another key feature of the polyolefin or more specifically polypropylene flat mesh is that its fibers may contain an antimicrobial agent or agents such as triclosan. Obviously, these applications did not deal with certain aspects of the intravaginal ring system which include the use of surface-activated, knitted, ringed-mesh having an average pore diameter exceeding 100 micron—this is well beyond an order-of-magnitude difference from the sperm head diameter of about 7 micron and higher than the previously disclosed mesh pore diameter described as being less than 100 micron.
Collectively, the prior art discussed above dealt with (1) totally absorbable or partially absorbable intravaginal ring constructs and was silent on new intravaginal rings that are biostable as is the case for the instant invention; (2) intravaginal, non-hormonal spermiostatic/spermicidal agents, but was silent on the use of simple non-hormonal organic drugs that are not prescribed as effective contraceptive agents, which was surprisingly found to be the case in parts of the instant invention; (3) intravaginal non-hormonal contraceptive rings, which also exhibit antifungal or antibacterial activities due to the incorporation of an antifungal or antibacterial agent along with the non-hormonal spermiostatic/spermicidal agent, ferrous gluconate, but silent on the use of one agent that is antifungal or antibacterial and that is also spermiostatic, as is uniquely the case of the instant invention; and (4) intravaginal rings that have either antimicrobial or antiviral activity through the independent effect of at least two separate agents, but silent on the use of one particular agent to achieve, simultaneously, both antimicrobial and antiviral (or retroviral) activities as is the case of the instant invention. Additionally, the prior art was silent on the use of one particular drug of known efficacy for one indication and yet, it exhibits activity for two additional functions as in the case of the present invention. These facts and recent findings in our laboratory on unique properties of antifungal, antibacterial, and antineoplastic agents prompted the pursuit of the study, subject of the present invention.